Furo (2,3d) pyrimidines

ABSTRACT

Compounds of the formula ##STR1## wherein R is alkyl of 1-4 carbon atoms, phenyl, or phenyl substituted by one or more halogen or trifluoromethyl, and Z is ##STR2## wherein R 1  is hydrogen, alkyl of 1-4C, 2,2-dimethyldioxolan-4-yl methyl, or 2,3-dihydroxy prop-1-yl, R 2  is ##STR3## wherein ##STR4## is morpholino, pyrrolidino, piperidino or hexamethyleneimino, and n is an integer from 4 to 7. 
     The compounds are prepared by reacting R-substituted 4-chloro-2-methyl furo (2,3d) pyrimidine with HZ. The compounds possess antiulcerous, antibronchoconstrictive and anticholinergic, analgesic, antihistamine, diuretic, cardiovascular analeptic, antiinflammatory and hypertensive properties.

This is a division of application Ser. No. 506,826, filed Sept. 17, 1974, now U.S. Pat. No. 4,007,187.

The present invention relates to novel furo (2,3d) pyrimidines, their process of preparation and their therapeutic application.

The compounds according to the invention correspond to the general formula: ##STR5## in which: R represents an alkyl radical containing up to 4 carbon atoms or a phenyl ring optionally substituted by one or more halogen atoms, or by a trifluoromethyl radical; and

Z represents one of the following: ##STR6## in which: R₁ represents a hydrogen atom, an alkyl radical containing up to 4 carbon atoms, a 2,2-dimethyl dioxolan-4-yl methyl radical or a 2,3-dihydroxy prop-1-yl radical,

R₂ represents: a β-amino ethoxy group of formula ##STR7## a carboxamide group of formula ##STR8## or a group of formula ##STR9## the symbol ##STR10## representing a morpholino, pyrrolidino, piperidino or a hexamethyleneimino radical, and

n is an integer of between 4 and 7.

The process according to the invention consists in condensing a 4-chloro-2-methyl furo (2,3d) pyrimidine of formula: ##STR11## in which R represents an alkyl radical containing up to 4 carbon atoms or a phenyl ring optionally substituted by one or more halogen atoms, or by a trifluoromethyl radical, with an amine derivative of formula III

    hz'                                                        (iii)

in which Z' represents one of the following: ##STR12## in which: R₁ ' represents a hydrogen atom, an alkyl radical containing up to 4 carbon atoms,

R₂ represents a β-amino ethoxy group of formula ##STR13## a carboxamide group of formula ##STR14## or a group of formula ##STR15## the symbol ##STR16## representing a morpholino, pyrrolidino, piperidino or a hexamethyleneimino radical, and

n is an integer of between 4 and 7.

to produce a derivative corresponding to the formula: ##STR17## and, optionally subjecting a derivative of the formula I' in which Z' represents a 2-methoxycarbonyl anilino radical, to a transesterification in the presence of sodium with 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane, to give the derivate of formula: ##STR18## which may be then transformed into a derivative of formula: ##STR19## by opening of the dioxolane cycle with hydrochloric acid.

It is to be noted that the condensation of the 4-chloro-2-methyl furo (2,3d) pyrimidines of formula (II) with the amine derivatives of formula (III) is conducted:

in benzene under reflux when Z' represents a ##STR20## radical, in which n is an integer of between 4 and 7, and in acetic acid, in the presence of catalytic quantities of concentrated hydrochloric acid, when Z' represents a radical ##STR21##

The following preparations are given, by way of example, to illustrate the invention.

EXAMPLE 1 2-methyl-4-pyrrolidino-6-(metatrifluoromethyl phenyl) furo (2,3d) pyrimidine (Code No. 72497)

14.2g (0.2 mol) of pyrrolidine was added, drop by drop, to a solution of 31.3g (0.1 mol) of 2-methyl-4-chloro-6-(metatrifluoromethyl phenyl) furo (2,3d) pyrimidine in 350 c.c. of benzene heated at 60° C, and the mixture was then refluxed for 6 hours. The mixture is filtered whilst warm, the filtrate is evaporated under vacuum, and the residue is recrystallised from methylethyl ketone.

Melting point = 203° C

Yield = 58%

Empirical formula = C₁₈ H₁₆ F₃ N₃ O

    ______________________________________                                         Elementary analysis:                                                                        C       H         N                                               ______________________________________                                         Calculated (%) 62.24     4.64      12.10                                       Found (%)      62.13     4.69      12.03                                       ______________________________________                                    

EXAMPLE 2 N-(2,6-dimethyl furo (2,3d) pyrimidin-4-yl) methyl anthranilate (Code No. 7280)

A suspension of 4.55 g. (0.03 mol) of methyl anthranilate, 5.45 g. (0.03 mol) of 2,6-dimethyl-4-chloro furo (2,3d) pyrimidino and 0.1 c.c. of concentrated hydrochloric acid in 30 c.c. of acetic acid were heated at 80° to 90° C for 30 minutes. The precipitate formed is filtered, placed in suspension with 50 c.c. of ethanol, alkalinised with concentrated ammonia, diluted with 200 c.c. of water, filtered, washed with water, recrystallised from ethanol and then from acetone.

Melting point = 186° C

Yield = 34%

Empirical formula = C₁₆ H₁₅ N₃ O₃

    ______________________________________                                         Elementary analysis:                                                                        C       H         N                                               ______________________________________                                         Calculated (%) 64.63     5.09      14.14                                       Found (%)      64.75     5.26      14.14                                       ______________________________________                                    

EXAMPLE 3 N-(2,6-dimethyl furo (2,3d) pyrimidin-4-yl)-4'-methyl-2',2'-dimethyl-1',3'-dioxolane anthranilate (Code No. 730 367)

0.3 g of sodium is dissolved, with warming, in 260 c.c. of 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane. After cooling, 65.5 g (0.22 mol) of N-(2,6-dimethyl furo (2,3d) pyrimidin-4-yl) methyl anthranilate of code No. 7280 obtained as indicated in the preceding example, is added thereto and the resultant mixture is heated for 5 hours at 140°-150° C, the methanol formed being distilled off under nitrogen. The mixture is diluted with 2l of water, filtered, washed with water and recrystallied from ethanol.

Melting point = 160° C

Yield = 50%

Empirical formula = C₂₁ H₂₃ N₃ O₅

    ______________________________________                                         Elementary analysis:                                                                        C       H         N                                               ______________________________________                                         Calculated (%) 63.46     5.93      10.57                                       Found (%)      63.42     5.95      10.37                                       ______________________________________                                    

EXAMPLE 4 4-(β,γ-2'-dihydroxypropoxycarbonyl-phen-1'yl amino)-2,6-dimethyl furo (2,3d) pyrimidine (Code No. 730 387)

A suspension of 58g (0.147 mol) or N-(2,6-dimethyl furo (2,3d) pyrimidin-4-yl)-4'-methyl-2',2'-dimethyl-1',3'-dioxolane anthranilate of Code No. 730 367 obtained as indicated in example 3, in 500 c.c. of 2N hydrochloric acid is heated for 45 minutes under reflux. The mixture is filtered whilst warm, neutralised with 100 c.c. of triethylamine, the precipitate formed is filtered, washed with water and recrystallised from ethanol.

Melting point = 179° C

Yield = 30%

Empirical formula = C₁₈ H₁₉ N₃ O₅

    ______________________________________                                         Elementary analysis:                                                                        C       H         N                                               ______________________________________                                         Calculated (%) 60.49     5.36      11.70                                       Found (%)      60.62     5.36      11.71                                       ______________________________________                                    

The compounds listed in the following Table I have been prepared according to the same mode of operation.

                                      TABLE I                                      __________________________________________________________________________      ##STR22##                                                                                                          Melting                                   Code                    Empirical                                                                             Molecular                                                                            Point                                                                              Yield                                                                             Elementary Analysis.               No.  R        Z         Formula                                                                               Weight                                                                               (° C)                                                                       %          C   H  N                   __________________________________________________________________________     72 498                                                                               ##STR23##                                                                               ##STR24##                                                                               C.sub.19 H.sub.18 F.sub.3 N.sub.3 O                                                   361.36                                                                               129 29 Calculated (%) Found                                                                   63.15 63.00                                                                        5.02 5.06                                                                         11.63 11.55         72 557                                                                               ##STR25##                                                                               ##STR26##                                                                               C.sub.18 H.sub.16 F.sub.3 N.sub.3 O.sub.2                                             363.33                                                                               178 42 Calculated (%) Found                                                                   59.50 59.36                                                                        4.44 4.49                                                                         11.57 11.67         72 535                                                                               ##STR27##                                                                               ##STR28##                                                                               C.sub.20 H.sub.20 F.sub.3 N.sub.3 0                                                   375.38                                                                               126 53 Calculated (%) Found                                                                   63.99 63.77                                                                        5.37 5.45                                                                         11.19 11.02         72 561                                                                               ##STR29##                                                                               ##STR30##                                                                               C.sub.21 H.sub.22 F.sub.3 N.sub.3 O                                                   389.41                                                                               145 45 Calculated (%) Found                                                                   64.77 64.74                                                                        5.69 5.77                                                                         10.79 10.35         71 334                                                                               ##STR31##                                                                               ##STR32##                                                                               C.sub.17 H.sub.16 ClN.sub.3 O                                                         313.78                                                                               186 43 Calculated (%) Found                                                                   65.07 64.89                                                                        5.14 5.15                                                                         13.39 13.22         72 544                                                                               ##STR33##                                                                               ##STR34##                                                                               C.sub.18 H.sub.18 Cl N.sub.3 O                                                        327.81                                                                               187 39 Calculated (%) Found                                                                   65.95 65.74                                                                        5.53 5.45                                                                         12.82 12.60         72 545                                                                               ##STR35##                                                                               ##STR36##                                                                               C.sub.17 H.sub.16 ClN.sub.3 O.sub.2                                                   329.78                                                                               226 29 Calculated (%) Found                                                                   61.91 62.01                                                                        4.89 4.87                                                                         12.74 12.36         72 700                                                                               ##STR37##                                                                               ##STR38##                                                                               C.sub.19 H.sub.20 Cl N.sub.3 O                                                        341.83                                                                               147 32 Calculated (%) Found                                                                   66.76 66.59                                                                        5.90 5.76                                                                         12.29 12.14         72 682                                                                               ##STR39##                                                                               ##STR40##                                                                               C.sub.20 H.sub.22 Cl N.sub.3 O                                                        355.86                                                                               126 24 Calculated (%) Found                                                                   67.50 67.48                                                                        6.23 6.26                                                                         11.81 11.96         730372                                                                              CH.sub.3                                                                                 ##STR41##                                                                               C.sub.15 H.sub.13 N.sub.3 O.sub.3                                                     283.28                                                                               260 39 Calculated (%) Found                                                                   63.59 63.50                                                                        4.63 4.82                                                                          14.83 15.03        740119                                                                              CH.sub.3                                                                            ##STR42##         C.sub.21 H.sub.24 N.sub.4 O.sub.4                                                    396.43                                                                             152                                                                               55 Calculated (%) Found                                                                   63.62 63.83                                                                        6.10 6.30                                                                         14.13 14.16         730 525                                                                             CH.sub.3                                                                            ##STR43##         C.sub.19 H.sub.20 N.sub.4 O.sub.2 + 1/2                                        H.sub.2 O                                                                            345.39                                                                             225                                                                               20 Calculated (%) Found                                                                   66.07 66.29                                                                        6.29 6.25                                                                         16.22 16.04         730508                                                                              CH.sub.3                                                                            ##STR44##         C.sub.19 H.sub.20 N.sub.4 O.sub.3                                                    352.38                                                                             200                                                                               44 Calculated (%)  Found                                                                  63.04 64.94                                                                        5.72 5.75                                                                         15.90 15.80         730693                                                                              CH.sub.3                                                                            ##STR45##         C.sub.20 H.sub.24 N.sub.4 O.sub.3                                                    368.42                                                                             134                                                                               62 Calculated (%) Found                                                                   65.20 65.15                                                                        6.57 6.76                                                                         15.21 15.25         __________________________________________________________________________

The compounds of formula I have been tested on animals in the laboratory and have been shown to possess antiulcerous, antibronchoconstrictive and anticholinergic, analgesic, antihistaminic, diuretic, cardiovascular analoptic, antiinflammatory and hypertensive properties.

1. Antiulcerous properties analgesic,

The compounds of formula I, administered by oral means, reduce the extent of gastric ulcers provoked in a rat by tying of the pylorus (Shay ulcers).

Thus, the compound of Code No. 72 498, administered in a dose of 50 mg/Kg/i.d., permits a reduction of 35% of the Shay ulcers in a rat.

2. Antibronchoconstrictive and anticholinergic properties

Injected by intraduodonal means, the compounds of formula I are capable of opposing the bronchoconstriction provoked in the guinea-pig by the intraveinous injection of acetylcholine and evaluated by the Kenzett method.

By way of example, the administration of 100 mg/Kg/i.d. of the compound of Code No. 72 544, permits an inhibition of 50% of the bronchoconstriction provoked in the guinea-pig by the intraveinous injection of acetylcholine.

3. Analgesic properties

The compounds of formula I, administered to the mouse or rat by oral means, are capable of reducing the number of painful stretchings caused by the intraperitoneal injection of acetic acid or phenylbenzoquinone and they protect the rat against crying or jumping in the Randall and Selitto test.

By way of example:

Table II lists the DE50 of different compounds according to the invention, and

Table III indicates the results obtained by the administration of 100 mg/Kg/po of other compounds of formula I.

                  Table II                                                         ______________________________________                                                     Code No. of                                                        Nature of   compound              DE 50                                        test effected                                                                              tested       Animal   (mg/Kg/po)                                   ______________________________________                                         Test with   730 387      mouse    80                                           phenylbenzo-             rat      43                                           quinone                                                                                    730 372      mouse    20                                                                    rat      52                                                       730 367      mouse    72                                                                    rat      95                                           Randall &   730 387      rat      42                                           Selitto                                                                        test                                                                                       730 372      rat      40                                           ______________________________________                                    

                  Table III                                                        ______________________________________                                                                 Percentage diminution of                               Nature of test                                                                            Code No. of  number of painful                                      effected   compound tested                                                                             stretchings (%)                                        ______________________________________                                         Test with  730 693      70                                                     acetic acid                                                                                72 545      70                                                     Test with                                                                      phenylbenzo-                                                                              730 508      60                                                     quinono                                                                        ______________________________________                                    

4. Antihistaminic properties

The compounds of formula I, introduced in the conserving medium, are capable of opposing the contractural action of histamine on the isolated ileon of the guinea-pig. This activity is evaluated taking promothazine as standard.

Thus, the compound of Code No. 72561 provides an anti-histaminic activity equivalent to 1/15th that of promethazine.

5. Diuretic properties

The compounds of formula I, administered by oral means to the mouse, simultaneously with a volume of 1 ml. of an isotonic solution of sodium chloride per 25g of the corporeal weight of the mouse, are capable of provoking an augmentation of the volume of urine emitted by reference to control animals, the volume being measured for 6 hours following administration.

Thus, the administration of 25 mg/Kg/po of the compounds of Code Nos. 730 508 and 730387 produced an augmentation of the urinary elimination by 70% and 55%, respectively.

6. Cardiovascular analeptic properties

These properties are shown by an augmentation of the force of contractions (positive inotrope action) in the isolated heart of the guinea-pig maintained in a conserving medium and under appropriate experimental conditions.

By way of example, the compounds of Code Nos. 730 387 and 730 372 respectively provoke an augmentation of 75% and of 50% in the force of contractions in a concentration of 0.5 μg/ml.

7. Antiinflammatory properties

The compounds of formula I administered to the rat by oral means, provoke a diminution of the local oedema caused by the sub-plantar injection of carraghenine or Kaolin and oppose the inflammation caused by the Freund adjuvant. Administered by oral means to the guinea-pig, they reduce the erytheme caused by ultra-violet irradiation:

The results are listed in the following table V

    __________________________________________________________________________            Reduction of                                                                              Protection against                                                                          Protection against                                     oedema with                                                                               erythema by  arthitis by                                            carraghenine                                                                              ultra-violet Freund adjuvant                                 Code No.                                                                              or Kaolin  Dose         Dose                                            of compound                                                                           DE 50      administered                                                                          Protection                                                                           administered                                                                          Protection                               tested (mg/Kg/po) (mg/Kg/po)                                                                            (%)   (mg/Kg/po)                                                                            (%)                                      __________________________________________________________________________     730 387                                                                               38(carraghenine)                                                                          100    60    --     --                                              27(carraghenine)                                                        730 372                                                                               27(carraghenine)        200    55                                               6(Kaolin) --     --                                                    730 367                                                                               47(carraghonine)                                                                          100    50    --     --                                       __________________________________________________________________________

Also, the administration of the compound of Code No. 730 367 in a dose of 100 mg/Kg/po permits a diminution by 75% of the local oedema caused by the injection of Kaolin.

8. Hypertonsive properties

Administered by intraveinous means, the compounds of formula I provoke an increase in the arterial pressure of an anaesthetised rat.

By way of example, the administration of the compound of Code No. 730 693 in a dose of 2 mg/Kg/i.v., provokes an increase an the arterial pressure of an anaesthetised rat by 25% for a period of the order of 30 minutes.

As a result of a comparison between the pharmacologically active doses mentioned above and the lethal doses listed in the following Table V, the difference between said doses is sufficiently great to permit the utilisation of the compounds of formula I in therapeutics.

    ______________________________________                                         Code No. of                                                                    compound    Dose administered                                                                            Percentage mortality                                 tested      (mg/Kg/po)    %                                                    ______________________________________                                         72 498      2000          0                                                    72 544      2000          0                                                    72 561      2000          0                                                    72 545      2000          0                                                    730 387     2000          0                                                    730 372     1500                                                                                          ##STR46##                                           730 367     2000          0                                                    730 508     2000          0                                                    730 693     2000                                                                                          ##STR47##                                           ______________________________________                                    

The compounds of formula I are useful in the treatment of gastro-duodenal ulcers, visceral spasms, asthma, diverse originating pains and painful inflammations, allergies, oedemas and hypotension.

They may be administered by oral means in the form of tablets, dragees and gelules, containing 50 to 500 mg. of active ingredient (one to six times a day), by parenteral means in the form of injectable ampoules containing 10 to 250 mg of active ingredient (one to three times a day) by rectal means in the form of suppositories containing 25 to 400 mg of active ingredient (one to three times a day) and in the form of suspensions containing 0.5 to 5% of active ingredient (20 to 60 drops, one to three times a day).

Accordingly, the present invention also relates to a therapeutic composition comprising a compound of the general formula I, together with a therapeutically acceptable carrier. 

What we claim is:
 1. A compound having the formula ##STR48## in which R is alkyl having one to 4 carbon atoms, phenyl, or phenyl substituted with at least one halogen or by a trifluoromethyl, andZ is ##STR49## in which R₂ is ##STR50## wherein ##STR51## is morpholino, pyrrolidino, piperidino or hexamethyleneimino.
 2. A compound as claimed in claim 1 in which R is CH₃ and Z is ##STR52##
 3. A compound as claimed in claim 1 in which R is CH₃ and Z is ##STR53## 